The objective of this proposed research is to define target gene(s) underlying predisposition to atherosclerosis and to develop human gene therapy for the treatment of hyperlipidemia. Studies will be carried out to define genetic factor(s) that contributes to atherosclerosis by developing dyslipidemia murine model. We will use these models to elucidate the molecular mechanisms of the disease and to evaluate novel therapeutics. The proposal seeks out to establish the effectiveness of using adeno-associated virus vector for gene delivery of ribozyme in diseased animals. Studies will also investigate the efficacy of using ribozyme as a potential therapeutic agent by generating transgenic mouse expressing ribozyme. Studies will also address new approaches for gene delivery of multiple genes together by using helper-dependent adenovirus vector in vivo to evaluate the synergistic effect of this strategy on the treatment for hyperlipidemia. Taken together, these studies will provide understanding of target(s) underlying predisposition to atherogenesis. The study will shed new insights to the understanding of the structure/function of the apoB mRNA hammerhead ribozyme, and the possible application of using this ribozyme as a therapeutic agent for the treatment of atherosclerosis.